Clinical TrialTreatment-Resistant Depression (TRD)PlaceboPsilocybinPlaceboPsilocybinPlaceboPsilocybinNot yet recruiting

Evaluating the efficacy of psilocybin-assisted psychotherapy in treatment resistant depression (EMPACT): A randomised, double blinded, 4 arm parallel adaptive trial

Randomised, double-blinded, Phase II adaptive 4-arm parallel trial (n=140) comparing three psilocybin regimens with dexamfetamine control; three oral dosing sessions (psilocybin 25 mg or dexamfetamine 7.5 mg) delivered 2–4 weeks apart with structured psychotherapy.

Target Enrollment
140 participants
Study Type
Phase II interventional
Design
Randomized, double Blind

Detailed Description

EMPACT is a four-arm, response-adaptive randomised trial in participants with treatment-resistant depression comparing three psilocybin dosing regimens to an active dexamfetamine control; participants receive up to three blinded oral dosing sessions (25 mg psilocybin or 7.5 mg dexamfetamine) spaced 2–4 weeks apart.

Each dosing session is supported by two preparation sessions (1–2 hours each) and integration sessions after each dose (plus a fourth integration after the final dose); therapists use an ACT-informed approach and trauma-informed supportive techniques.

Primary outcomes include change in HAM-D at baseline versus 1, 3 and 6 months post final PAP cycle; the adaptive design uses response-adaptive randomisation after the initial 50 participants with interim analyses for efficacy or futility.

Study Protocol

Preparation

2 sessions
90 min each

Dosing

3 sessions
480 min each

Integration

4 sessions
90 min each

Therapeutic Protocol

act

Study Arms & Interventions

Dexamfetamine

active comparator

Control arm: dexamfetamine 7.5 mg at each treatment session (three sessions).

Interventions

  • Placebo7.5 mg
    via Oral• three doses (2-4 weeks apart)• 3 doses total

    Dexamfetamine 7.5 mg (active comparator; actual compound recorded in notes).

Mixed B

experimental

Combined regimen with dexamfetamine and psilocybin across three sessions (arm-specific schedule).

Interventions

  • Psilocybin25 mg
    via Oral• three doses (2-4 weeks apart)• 3 doses total

    Psilocybin 25 mg in some sessions per arm allocation.

  • Placebo7.5 mg
    via Oral• three doses (2-4 weeks apart)• 3 doses total

    Dexamfetamine 7.5 mg in other sessions; mixed schedule per arm.

Mixed C

experimental

Combined regimen with dexamfetamine and psilocybin across three sessions (alternate mixed schedule).

Interventions

  • Psilocybin25 mg
    via Oral• three doses (2-4 weeks apart)• 3 doses total

    Psilocybin 25 mg in some sessions per arm allocation.

  • Placebo7.5 mg
    via Oral• three doses (2-4 weeks apart)• 3 doses total

    Dexamfetamine 7.5 mg in other sessions; mixed schedule per arm.

Psilocybin

experimental

Active arm: psilocybin 25 mg at each treatment session (three sessions).

Interventions

  • Psilocybin25 mg
    via Oral• three doses (2-4 weeks apart)• 3 doses total

    Psilocybin 25 mg oral capsule at each session.

Participants

Ages
18 – 80
Sexes
Male & Female

Inclusion Criteria

  • Diagnosis of a major depressive episode (MDE) in accordance with the Mini International Neuropsychiatric Interview (MINI)
  • Treatment resistant symptoms at Stage II of the Thase and Rush classification: failure to tolerate minimum of two trials of antidepressant medication at minimum effective therapeutic dose for at least 6 weeks
  • HAM-D score >17 (moderate–severe depression)
  • Capacity to give informed consent
  • Willingness and capacity to engage in the therapeutic elements of the protocol

Exclusion Criteria

  • Unable to give adequate informed consent
  • Current or previous psychotic disorder, schizophrenia or bipolar disorder
  • Immediate family member with a diagnosed psychotic disorder
  • Significant history of mania
  • History of serious suicide attempts in recent years requiring hospitalisation as judged by study psychiatrist
  • Psychiatric condition judged incompatible with rapport or safe exposure to psilocybin (e.g., borderline personality disorder)
  • Medically significant condition unsuitable for the study (e.g., unstable diabetes, moderate–severe hepatic or renal failure, severe cardiovascular disease)
  • QT prolongation at screening (QTc >440 ms men, >470 ms women) or history of ventricular arrhythmia
  • Wolff–Parkinson–White or uneliminated accessory pathway
  • Epilepsy
  • Moderate–severe previous or current head injury/TBI
  • History of stroke or TIA
  • Current moderate–severe drug or alcohol dependence within 12 months
  • Positive pregnancy test, planning pregnancy or breastfeeding; unwillingness to use acceptable contraception
  • Nicotine dependence preventing abstinence during dosing period
  • Recreational psychedelic use in last 12 months or history of regular psychedelic use
  • No email access or unwillingness to engage in electronic follow-up
  • Use of contraindicated medications including MAOI, SSRI or SNRI (withdrawal windows apply)
  • BMI <17 or >42

Study Details

Locations

Unknown facility — Australia

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